Event Details

Although serum from Parkinson’s disease (PD) patients displays elevated levels of numerous pro-inflammatory cytokines including IL-6, TNFa, IL-1ß, and IFNg, whether inflammation contributes to or is a consequence of neuronal loss remains unknown1. Mutations in Parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early-onset PD2,3. Working in the same biochemical pathway, PINK1 and Parkin remove damaged mitochondria from cells in culture and in animal models via a selective form of autophagy, called mitophagy4. The role of mitophagy in vivo, however, is unclear in part because mice lacking PINK1 or Parkin have no substantial PD-relevant phenotypes, in contrast to man and Drosophila 5-7. As mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity8-14, we examined if mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Parkin-/- and PINK1-/- mice following exhaustive exercise (EE) and in Parkin-/-;Mutator mice, which accumulate mitochondrial DNA mutations with age15. Inflammation resulting from both EE and mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the Type-I Interferon response to cytosolic DNA16,17. A motor defect observed in aged Parkin-/-; Mutator mice is also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. These results support an unanticipated function for PINK1- and Parkin-mediated mitophagy and a novel link to PD.